DESCRIPTION Neurofibrillary degeneration is a hallmark of Alzheimer's disease and is a recognized pathological diagnostic tool. Whether this degeneration is a cause of AD or is a manifest side effect remains unclear. However, since it does represent a potential target of therapeutic intervention, it is important to determine mechanistically how this process progresses. The U.S. lab has devoted several years to the study of the microtubule associated protein, Tau, and how abnormally phosphorylated Tau might contribute to microtubule disassembly and paired helical filament formation in the AD afflicted brain. While a visiting scientist in the U.S. lab the proposed foreign collaborator studied the phosphorylation states of Tau, and showed how dephosphorylation could restore normal Tau function. She also showed that Tau is glycated in the AD brain, but not under normal circumstances. The present collaboration will extend these findings to examine if posttranslational modifications of neurofilament proteins, phosphorylation and glycation, might also play an important role in neurofibrillary degeneration. Specifically, the U.S. site will bulk isolate somatodendritic and axonal neurofilaments from normal and AD brains and the foreign site will 1) further subfractionate individual NF subunits and determine their degrees of glycation and phosphorylation and 2) determine the role of neurofilament alterations in their interactions with normal tau, hyperphosphorylated Tau as related to microtubule assembly.